1. Technical Field
The present invention relates to a pharmaceutical composition for preventing or treating tuberculosis based on the inhibition on carbon monoxide dehydrogenase in Mycobacterium tuberculosis. 
2. Background Art
Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis. Tuberculosis is one of the main diseases in developing countries and its seriousness has been increased also in advanced countries. Approximately 8 million new patients are found and approximately 3 million patients die each year. Tuberculosis may be asymptomatic for a considerable period of time even after infection. However, this disease commonly gives rise to acute inflammation of the lungs and then thermal and non-productive cough. Moreover, tuberculosis, if not treated, may typically cause serious complications, leading to death.
Recently, Mycobacterium tuberculosis has grown in importance since some cases of infection with Mycobacterium tuberculosis strains having resistance against both the HIV pandemic and several kinds of drugs have been reported. According to the researches on antibiotic-resistant Mycobacterium tuberculosis over last five years in 35 countries, Mycobacterium tuberculosis having resistance to one or more drugs is approaching 36%, and multidrug-resistant Mycobacterium tuberculosis (MDR-TB), which shows resistance to two or more antibiotics including rifampin (RMP), is about 36%. These figures indicate serious levels. Approximately 9.9% of patients even without a history of tuberculosis treatment show resistance to at least one drug. As such, drug-resistant tuberculosis and multi-drug resistant tuberculosis increase treatment costs as well as lower treatment efficiency, and eventually become a great threat to patients, such as developing into incurable tuberculosis. The existing tuberculosis treatments generally require a long period of time, one to two years. Here, combined administration of three or four drugs is recommended since the use of one or two antitubercular agents induces fast resistance. However, the long-term use of antitubercular agents strains the liver, causing side effects, such as liver cirrhosis and jaundice. Moreover, for the treatment of multi-drug resistant tuberculosis, secondary antitubercular agents, which are relatively less effective, induce more side effects, and are expensive, need to be used. Accordingly, for the tuberculosis elimination strategy for improving treatment efficiency of the multi-drug resistant tuberculosis, new drugs capable of treating even latent tuberculosis, being more effective, having less side effects, and exhibiting efficacy for a short period of time are required to be developed.
Although antitubercular agents that are harmless to humans, more effective, and act quickly are urgently required to be developed as described above, the currently developed drugs do not exhibit great effects in tuberculosis treatment.
However, the DNA sequence of Mycobacterium tuberculosis was established, which opened the possibility to find targets of new drugs. Recently, an inhibitor against expression and activation of carbon monoxide dehydrogenase (CO-DH) is emerging as a new tuberculosis treatment agent.
In general, macrophages inhibit bacterial multiplication through various methods, which include a method in which phagolysosome formed by the fusion of phagosome with lysosome uses protease in the lysosome to remove microorganisms and a method in which bactericidal reactive oxygen and nitrogen species secreted by IFN-γ stimulation remove microorganisms. The reactive nitrogen species is the key material in innate immunity. The reactive nitrogen species contains NO and its derivatives. NO is produced from the degradation of L-arginine by inducible nitric oxide synthase (iNOS). NO derivatives, such as HNO2 and HNO3, play an important role in the control of intracellular parasitic bacteria such as Mycobacterium tuberculosis and the like, or cancer cells. Here, Mycobacterium tuberculosis survives against various bactericidal mechanisms of macrophages, causing diseases in hosts.
Meanwhile, carboxydobacteria are a group of bacteria which are able to grow by using carbon monoxide (CO) as the sole energy and carbon source. The main enzyme for the oxidation of CO in the carboxydobacteria is CO-DH. CO-DH oxidizes CO into carbon dioxide (CO2) to generate two electrons by using water as an oxidant. Here, CO2 is converted into cellular components through the Calvin cycle, and the electrons are used to energy production through oxidative phosphorylation in the electron transport chain.
It was recently founded that Mycobacterium sp. strain JC1, which is evolutionarily far away from the known carboxydobacteria, has CO-DH activity, and CO-DH genes were cloned and DNA-sequenced therefrom. This facilitates the study of CO-DH activities for various species of the genus Mycobacterium, and it was found that, besides Mycobacterium sp. strain JC1, many species exhibit CO-DH activity. In addition, gene sequencing of some of the previously identified mycobacteria, including Mycobacterium tuberculosis H37Rv, revealed that open reading frames (OFRs) similar to those of the CO-DH genes of Mycobacterium sp. strain JC1 are conserved in these bacteria. In CO-DH genes of the mycobacteria, three genes seem to be clustered in the order of cutB-cutC-cutA to constitute one operon.
In addition, CO-DH activity on NO was studied from the understanding of structural similarity between CO and NO used as substrates of CO-DH. As a result, it was observed that CO-DH also possesses activity of nitric oxide dehydrogenase (NO-DH) that uses NO as a substrate.
Based on the existing studies, in order to find the relation between NO-DH activity that is exhibited by CO-DH and the intramacrophage survival mechanism of Mycobacterium tuberculosis, the present inventors constructed mutants of several species of mycobacteria including Mycobacterium tuberculosis H37Rv with respect to CO-DH genes, and established intramacrophage survival-associated characteristics of the mutants.
As a result, in the case of Mycobacterium tuberculosis H37Rv, CO-DH activity was observed in only the wild type but not the mutant. Further, it was verified that the intramacrophage survival rate was remarkably reduced in the mutant of Mycobacterium tuberculosis H37Rv as compared with the wild type.
These results present a new approach to safe antitubercular agents capable of promoting a complete cure of tuberculosis and reducing tissue damages by inhibiting metabolisms associated with the survival of Mycobacterium tuberculosis to suppress survival and growth of Mycobacterium tuberculosis. 
Throughout the entire specification, many papers and patent documents are referenced and their citations are represented. The disclosures of cited papers and patent documents are entirely incorporated by reference into the present specification, and the level of the technical field within which the present invention falls and details of the present invention are explained more clearly.